When to start antiretroviral therapy (ART) and what to start represent key ongoing issues in HIV care. While these questions have been asked for the outcomes of AIDS and all-cause mortality, they now need to be extended to other serious outcomes, including cancer, which has endured as a major cause of morbidity and mortality for HIV-infected patients. The overarching goal of the current proposal is to formulate evidence-based recommendations about the preferred CD4 T-cell count at which to initiate ART, and the preferred initial ART regimen, that would minimize cancer incidence among HIV-infected persons. We will conduct this research within the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), which includes 22 diverse HIV cohorts in the U.S. and Canada with more than 100,000 HIV-infected patients, validated cancer diagnoses, and up to 15 years of follow-up. We will focus on three cancer groups as primary outcomes: AIDS- defining cancers, virus-related non-AIDS-defining cancers (NADC), and virus-unrelated NADC. We propose these grouped primary endpoints because their large Ns provide good statistical power and because clinical decisions about when and what to start might be based more on effects on cancer incidence for aggregated related cancers than on effects on incidence of individual cancer types. We also will consider 14 specific cancer types/groups as secondary outcomes. We propose to achieve two complementary and interrelated specific aims. The first aim will use a restricted sample of NA-ACCORD to emulate randomized controlled trials of ART for reducing cancer risk using causal statistical methodologies. This aim will evaluate the effect of the timing and composition of the initial ART regimen on the incidence of our primary and secondary cancer outcomes and includes two sub-aims: Aim 1a will evaluate whether initiation of ART at higher CD4 thresholds is associated with reduced incidence compared with initiation of ART at lower CD4 thresholds; Aim 1b will determine whether cancer incidence varies for the major ART classes and more common individual ART medications. The second aim will use the entire NA-ACCORD sample to elucidate the underlying relationships between patterns of immune suppression, HIV virus replication and incidence of our primary and secondary cancer outcomes and also has two sub-aims: Aim 2a will examine relationships between cancer risk and cumulative and current CD4 count and HIV RNA; Aim 2b will evaluate whether ART use, specific ART classes, or more common individual ART medications have an effect on cancer risk independent of the effect mediated by measures of CD4 count and HIV RNA found to be key predictors of cancer risk in Aim 2a. NA-ACCORD provides an ideal platform for conducting this study, with its diverse cohorts, large sample size, validated cancer diagnoses, longitudinal data on CD4 count, HIV RNA, and ART use, data on traditional cancer risk factors, efficient structure for harmonization of data, and high level of multidisciplinary expertise of collaborating investigators.